The overall objective of this project is mathematical modeling and computer simulation of fluid and electrolyte disorders in kidney tubules. To date, this project has formulated models of glomerulus, proximal convoluted tubule, and all segments from ascending Henle limb, through distal tubule, and collecting duct. In the next investigational period, the first task is to complete the library of renal segmental models, and fashion short- and long-looped nephrons, solved against interstitial composition. These models will simulate axial interaction among segments, as in osmotic diuresis or acetazolamide action, and predict the impact of medullary K+ concentration on distal solute delivery. Solved iteratively, this model will allow representation of the stabilization of distal solute delivery via tubuloglomerular feedback. The second aim will require the major investment of effort for the project period, and this will be to advance the nephron models from a specified interstitium to solving for interstitial concentrations as unknown variables. This aspect of the project is critical to estimating the impact of changing flows and changing transport on peritubular conditions. It extends the classical computational approach to the urine concentrating mechanism, to K+ and acid-base metabolism. Major metabolic derangements, such as hyperkalemia and acidosis, alter renal medullary solutes and thus influence urine composition; this will be the first effort to simulate that impact. The third aim will be to examine cellular homeostasis as a systems approach to cell membrane transporters. The approach will use mathematical control theory to identify transporter ensembles, which can function in a coordinated way to allow large re-absorptive fluxes, while preserving cell volume and composition. These transporter ensembles maybe viewed as hypothesis generation with respect to experimental examination of kidney tubules. Finally, experimental collaborations are in progress to examine predictions from this project. Work continues with Dr. Tong Wang to examine flow-dependent proximal tubule transport, specifically our proposal that brush border microvilli are flow mechanosensors. Anew project is planned with Dr. Wang to examine flow-dependent transport in distal nephron, specifically in relation to flow-dependent HCO-3 re-absorption as a consequence of diuretic ad- ministration. Genetic disorders of electrolyte metabolism or pharmacologic intervention general- ly affect a single transporter in a single kidney tubule. However, the impact on overall kidney function maybe far-reaching, affecting other segments, both adjacent and at a distance. Such models can rationalize whole-organ malfunction as the consequence of a molecular defect.